Hydroxamic acid derivatives as metalloproteinase inhibitors

ABSTRACT

Compounds of formula (I) have matrix metalloproteinase inhibitory activity, wherein R 2  represents a group R 6  --A-- wherein A represents a divalent straight or branched, saturated or unsaturated hydrocarbon chain of up to 6 C atoms which may be interrupted by an O or S atom, and R 6  represents hydrogen or an optionally substituted phenyl, cycloalkyl or cycloalkenyl group; R 3  represents a group R 7  --(B) n  -- wherein n is 0 or 1, B represents a divalent straight or branched, saturated or unsaturated hydrocarbon chain of up to 6 C atoms which may be interrupted by an O or S atom, and R 7  is --CONHOH, carboxyl, esterified or amidated carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, phenyl, naphtyl, or substituted phenyl or naphtyl in which the substituent(s) are selected from phenyl, hydroxy, C 1  -C 6  alkoxy, benzyloxy, or R 8  --(C═O)--(C 1  -C 6  alkyl)--O-- wherein R 8  is hydroxy, amino, or an amino acid residue linked via an amide bond; or (except when n=0) R 7  is hydrogen; R 4  represents hydrogen or methyl; R 5  represents hydrogen, C 1  -C 6  alkyl or a group D-(C 1  -C 6  alkyl) wherein D represents hydroxy, (C 1  -C 6 )alkoxy, (C 1  -C 6 )alkylthio, acylamino, optionally substituted phenyl, or a heterocyclic group, NH 2 , or a mono- or di-(C 1  -NC 6  alkyl) amine or a heterocyclic group; or R 3  and R 5  taken together represent a divalent, saturated or unsaturated hydrocarbon chain of from 8-14 C atoms, which may be interrupted by an O, S or N heteroatom, or a salt, solvate or hydrate thereof, provided that R 3  is not the characteristic side chain of a natural alpha-amino acid, or the characteristic side chain of a natural alpha-amino acid in which any functional substituents are protected, any amino groups are acylated, and any carboxyl groups are esterified.

This case is a 371 of PCT/GB93/01557 filed on Jul. 23, 1993.

The present invention relates to therapeutically active hydroxamic acidderivatives, to processes for their preparation, to pharmaceuticalcompositions containing them, and to the use of such compounds inmedicine. In particular, the compounds are inhibitors ofmetalloproteinases involved in tissue degradation, and in addition areinhibitors of the release of tumor necrosis factor from cells.

Compounds which have the property of inhibiting the action ofmetalloproteinases involved in connective tissue breakdown such ascollagenase, stromelysin and gelatinase (known as "matrixmetalloproteinases", and herein referred to as MMPs) are thought to bepotentially useful for the treatment or prophylaxis of conditionsinvolving such tissue breakdown, for example rheumatoid arthritis,osteoarthritis, osteopenias such as osteoporosis, periodontitis,gingivitis, corneal epidermal or gastric ulceration, and tumormetastasis, invasion and growth.

Tumour necrosis factor (herein referred to as "TNF") is a cytokine whichis produced initially as a cell-associated 28 kD precursor. It isreleased as an active, 17 kD form, which can mediate a large number ofdeleterious effects in vivo. When administered to animals or humans itcauses inflammation, fever, cardiovascular effects, haemorrhage,coagulation and acute phase responses, similar to those seen duringacute infections and shock states. Chronic administration can also causecachexia and anorexia. Accumulation of excessive TNF can be lethal.

There is considerable evidence from animal model studies that blockingthe effects of TNF with specific antibodies can be beneficial in acuteinfections, shock states, graft versus host reactions and autoimmunedisease. TNF is also an autocrine growth factor for some myelomas andlymphomas and can act to inhibit normal haematopoiesis in patients withthese tumors.

Compounds which inhibit the production or action of TNF are thereforethought to be potentially useful for the treatment or prophylaxis ofmany inflammatory, infectious, immunological or malignant diseases.These include, but are not restricted to, septic shock, haemodynamicshock and sepsis syndrome, post ischaemic reperfusion injury, malaria,Crohn's disease, mycobacterial infection, meningitis, psoriasis,congestive heart failure, fibrotic disease, cachexia, graft rejection,cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis,radiation damage, toxicity following administration of immunosuppressivemonoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolarinjury.

Since excessive TNF production has been noted in several diseases orconditions also characterised by MMP-mediated tissue degradation,compounds which inhibit both MMPs and TNF production may have particularadvantages in the treatment or prophylaxis of diseases or conditions inwhich both mechanisms are involved.

Several classes of MMP inhibitors have been proposed, includingderivatives of hydroxamic acid. The following patent publicationsdisclose hydroxamic acid-based MMP inhibitors:

U.S. Pat. No. 4,599,361 (Searle)

EP-A-0236872 (Roche)

EP-A-0274453 (Bellon)

WO 90/05716 (British Bio-technology)

WO 90/05719 (British Bio-technology)

WO 91/02716 (British Bio-technology)

EP-A-0489577 (Celltech)

EP-A-0489579 (Celltech)

EP-A-0497192 (Roche)

WO 92/13831 (British Bio-technology)

WO 92/22523 (Research Corporation Technologies)

WO 93/09090 (Yamanouchi)

The intrinsic potency of compounds within the broad structural groups ofhydroxamic derivatives disclosed in the above publications againstparticular MMPs can be high. For example, many have a collagenase IC₅₀by the in vitro test method of Cawston and Barrett, (Anal. Biochem., 99,340-345, 1979) of less than 50 nM. Unfortunately, however, thephysicochemical and/or pharmacokinetic properties of the specificcompounds disclosed in those publications have generally beendisappointing. Identifying hydroxamic acid-based MMP inhibitors having agood balance of high intrinsic activity against the target MMPs, andgood physicochemical and/or pharmacokinetic properties, such that thecompounds are easily formulated for administration, have goodbioavailability for acceptable periods following administration, andhave high in vivo activity in the target disease or condition, remains amuch sought after goal in the art.

The above patent publications disclose nothing concerning the inhibitionof TNF release. Indeed it appears that the state of the art as a wholedoes not include the recognition of anti-TNF properties in anyMMP-inhibiting hydroxamic acid derivatives.

The hydroxamic acid derivatives disclosed in the above publications canbe regarded as having the following basic structure (IA): ##STR1##wherein the five substituents R₁ -R₅ may vary according to the detaileddisclosure of each publication. The balance of intrinsic level ofactivity, degree of specificity of inhibition of particular categoriesof MMP, physicochemical and pharmacokinetic properties can vary in anunpredictable way as the substituents R₁ -R₅ are varied.

Of the above publications, only EP-A-0236872 refers to the possibilitythat in a particular class of collagenase inhibitors of basic structure(IA) the substituent R₁ may be OH. That possibility is referred toamongst many other possible R₁ substituents, in the context of compoundsin which the substituent R₃ is the characteristic side chain of anaturally occurring amino acid in which any functional substituents maybe protected, any amino group may be acylated, and any carboxyl groupmay be esterified. EP-A-0236872 does not disclose such compounds ashaving preferred or particularly advantageous collagenase inhibitoryproperties, and in fact contains no disclosure of any specific compoundin which R₁ is hydroxy. It does not address the problem in the artreferred to above of providing hydroxamic acid derived MMP inhibitorshaving the elusive balance of good intrinsic activity profile and goodphysicochemical and pharmacokinetic properties.

This invention makes available a novel group of compounds of generalformula (IA), principally characterised in that the R₁ substituent is ahydroxy group and in which the selected substituent R₃ is not the sidechain of a natural amino acid. It has been found that such compoundshave in general the sought after but unpredictable combination ofdesirable formulation characteristics, including good water-solubility,as well as desirable activity profiles as inhibitors of MMP's, includingboth collagenase and stromelysin inhibitory activity. The class includescompounds which achieve high serum levels following oral administration,and which are active in vivo following oral administration in relevantanimal models of diseases and conditions mediated by MMP's. Furthermore,as mentioned above, compounds of the invention have been found to havethe unexpected and desirable property of inhibiting TNF production.

According to one aspect of the present invention, there is provided acompound of formula (I): ##STR2## wherein R₂ represents a group R₆ --A--wherein A represents a divalent straight or branched, saturated orunsaturated hydrocarbon chain of up to 6 C atoms which may beinterrupted by an O or S atom, and R₆ represents hydrogen or anoptionally substituted phenyl, cycloalkyl or cycloalkenyl group;

R₃ represents a group R₇ --(B)_(n) -- wherein n is 0 or 1, B representsa divalent straight or branched, saturated or unsaturated hydrocarbonchain of up to 6 C atoms which may be interrupted by an O or S atom, andR₇ is --CONHOH, carboxyl, esterified or amidated carboxyl, cycloalkyl,cycloalkenyl, heterocyclyl, phenyl, napthyl, or substituted phenyl ornapthyl in which the substituent(s) are selected from phenyl, hydroxy,C₁ -C₆ alkoxy, benzyloxy, or R₈ --(C═O)--(C₁ -C₆ alkyl)--O-- wherein R₈is hydroxy, amino, or an amino acid residue linked via an amide bond; or(except when n=0) R₇ is hydrogen;

R₄ represents hydrogen or methyl;

R₅ represents hydrogen, C₁ -C₆ alkyl or a group D-(C₁ -C₆ alkyl) whereinD represents hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkylthio, acylamino,optionally substituted phenyl, or a heterocyclic group, NH₂, or a mono-or di-(C₁ -C₆ alkyl) amine or a heterocyclic group;

or R₃ and R₅ taken together represent a divalent, saturated orunsaturated hydrocarbon chain of from 8 to 16 C atoms, which may beinterrupted by an O, S or N heteroatom,

or a salt, solvate or hydrate thereof,

provided that R₃ is not the characteristic side chain of a naturalalpha-amino acid, or the characteristic side chain of a naturalalpha-amino acid in which any functional substituents are protected, anyamino groups are acylated, and any carboxyl groups are esterified.

As used herein the term "C₁ -C₆ alkyl" or "saturated hydrocarbon chainof up to 6 C atoms" refers to a straight or branched chain alkyl moietyhaving from 1 to 6 carbon atoms, including for example, methyl, ethyl,propyl, isopropyl, butyl, t-butyl, pentyl and hexyl.

The term "C₂ -C₆ alkenyl" or "unsaturated hydrocarbon chain of up to 6 Catoms" refers to a straight or branched chain alkenyl moiety having from2 to 6 carbon atoms and having in addition one double bond of either Eor Z stereochemistry where applicable. This term would include, forexample, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl.

The term "cycloalkyl" refers to a saturated alicyclic moiety having from3-8 carbon atoms and includes, for example, cyclohexyl, cyclooctyl,cycloheptyl, cyclopentyl, cyclobutyl and cyclopropyl.

The term "cycloalkenyl" refers to an unsaturated alicyclic moiety havingfrom 3-8 carbon atoms and includes, for example, cyclohexenyl,cyclooctenyl, cycloheptenyl, cyclopentenyl, cyclobutenyl andcyclopropenyl. In the case of cycloalkenyl rings of from 5-8 carbonatoms, the ring may contain more than one double bond.

The term "heterocyclyl" or "heterocyclic" refers to a 5-7 memberedheterocyclic ring containing one or more heteroatoms selected from S, Nand O, and optionally fused to a benzene ring, including for example,pyrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl,pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperizinyl, indolyland benzimidazole.

Unless otherwise specified in the context in which it occurs, the term"substituted" as applied to any moiety herein means substituted with upto four substituents, each of which independently may be C₁ -C₆ alkoxy,hydroxy, thio, C₁ -C₆ alkylthio, amino, halo (including fluoro, chloro,bromo and iodo), trifluoromethyl, nitro, --COOH, --CONH₂ or --CONHR^(A)wherein R^(A) is a C₁ -C₆ alkyl group or the residue of a naturalalpha-amino acid.

The term "characteristic side chain of a natural alpha-amino acid" meansthe characteristic side chain attached to the --CH(NH₂)(COOH) moiety inthe following amino acids: glycine, alanine, valine, leucine,isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine,cysteine, methionine, asparagine, glutamine, lysine, histidine,arginine, glutamic acid and aspartic acid.

Where a carboxylic acid group is esterified in compounds of formula (I),the notional esterifying moiety may be, for example, a C₁ -C₆ alkanol orbenzyl alcohol.

Where a carboxylic acid group is amidated in compounds of formula (I),examples include aminocarbonyl, (C₁ -C₆ alkyl)aminocarbonyl, di(C₁ -C₆alkyl)aminocarbonyl, and benzylaminocarbonyl groups, as well ascarboxylic acid groups amidated with an aminocarboxylic acid such as anatural alpha amino acid (e.g. glycine, alanine etc).

Salts of the compounds of the invention include physiologicallyacceptable acid addition salts for example hydrochlorides,hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates,phosphates, acetates, citrates, succinates, lactates, tartrates,fumarates and maleates. Salts may also be formed with bases, for examplesodium, potassium, magnesium, and calcium salts.

There are several chiral centres in the compounds according to theinvention because of the presence of asymmetric carbon atoms. Thepresence of several asymmetric carbon atoms gives rise to a number ofdiastereomers with R or S stereochemistry at each chiral centre. Generalformula (I), and (unless specified otherwise) all other formulae in thisspecification are to be understood to include all such stereoisomers andmixtures (for example racemic mixtures) thereof.

In the compounds of the invention, the preferred stereochemistry is ingeneral as follows:

C atom carrying the hydroxy group and hydroxamic acid moiety --S,

C atom carrying the R₂ group --R,

C atom carrying the R₃ group --S,

but mixtures in which the above configurations predominate are alsocontemplated.

In the compounds of the invention:

R₂ may for example be a C₃ -C₆ alkyl, cycloalkyl(C₃ -C₆ alkyl),phenyl(C₂ -C₆ alkyl), C₂ -C₄ alkoxy(C₁ -C₃ alkyl)_(m), or C₂ -C₄alkylsulphanyl(C₁ -C₃ alkyl)_(m) group wherein is 0 or 1. Examples ofparticular R₂ groups include iso-butyl, n-pentyl, cyclohexylpropyl,cyclohexylbutyl, cyclohexylpentyl, phenylethyl, phenylpropyl,phenylbutyl, phenylpentyl, propyloxymethyl, and propylsulphanyl.Presently preferred are compounds in which R₂ is iso-butyl;

(always subject to the proviso that R₃ is not the characteristic sidechain of a natural alpha-amino acid, or the characteristic side chain ofa natural alpha-amino acid in which any functional substituents areprotected, any amino groups are acylated, and any carboxyl groups areesterified), R₃ may for example be a phenyl, C₁ -C₆ alkyl, C₂ -C₆alkenyl, phenyl(C₁ -C₆ alkyl), substituted phenyl(C₁ -C₆ alkyl),cycloalkyl, cycloalkyl(C₁ -C₆ alkyl), thienyl, thienyl(C₁ -C₆ alkyl),pyridyl(C₁ -C₆ alkyl), thiazolyl(C₁ -C₆ alkyl), thiofuranyl(C₁ -C₆alkyl), benzothiofuranyl(C₁ -C₆ alkyl) or imidazolyl(C₁ -C₆ alkyl)group, or R₃ and R₅ taken together may form a C₇ -C₁₂ alkylene chain,optionally interrupted by an O, S or N heteroatom. Examples ofparticular R₃ groups include phenyl, t-butyl, cyclohexylpropyl,cyclohexylbutyl, cyclohexylpentyl, optionally substituted phenylethyl,phenylpropyl, phenylbutyl and phenylpentyl in which the optionalsubstituent(s) are in the phenyl ring and are selected from phenyl,hydroxy, C₁ -C₆ alkoxy, benzyloxy, tetrafluoromethyl, halo (e.g. chloro)and R₈ --(C═O)--(C₁ -C₆ alkyl)--O-- wherein R₈ is hydroxy, amino, or anamino acid residue linked via an amide bond. Other examples ofparticular R₃ groups include phenylethyl, cyclohexyl, thienyl(C₁ -C₆alkyl), pyridylmethyl, thiazolylmethyl, thiofuranylmethyl,benzothiofuranylmethyl or imidazolylmethyl, 1-ethenyl, 1-propenyl,1-propynyl, 2,2-dimethylpropyl, napthyl, napthylmethyl, propyloxymethyl,butyloxymethyl, and propylsulphanylmethyl, and butylsulphanylmethyl.Presently preferred are compounds in which R₃ is cyclohexylmethyl,t-butyl, 2-thienylmethyl, (4-hydroxycarbonylmethoxy)phenylmethyl,(4-phenyl)phenylmethyl, methoxycarbonylethyi, andN-hydroxyaminocarbonylethyl;

R₄ may for example be hydrogen, methyl or ethyl. Presently preferred arecompounds in which R₄ is hydrogen;

R₅ may for example be hydrogen or C₁ -C₄ alkyl, or a group D-(C₁ -C₆alkyl)

wherein D represents hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkylthio,acylamino, optionally substituted phenyl, or a heterocyclic group.Examples of particular R₅ groups include methyl, ethyl, propyl, butyl,hydroxyethyl, 2-ethylthioethyl, 2-acetoxyethyl, N-acetyl-2-aminoethyl,3-(2-pyrrolidone)propyl, optionally substituted phenylethyl,phenylpropyl, phenylbutyl and phenylpentyl, Presently preferred arecompounds in which R₅ is methyl or ethyl.

Interesting compounds of the invention are:

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-oxymethylcarboxy)phenylalanine-N¹ -methylamide;

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-phenyiglycine-N.sup.1-methylamide;

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-phenyl)phenylalanine-N¹-methylamide;

N³ -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!amino-1-azacyclotridecan-2-one;

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(1-pyrazolyl)alanine-N¹-methylamide;

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-4-(N-hydroxyamino)glutamicacid-N¹ -methylamide;

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(2-thienyl)alanine-N¹-methylamide;

N² - 3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹ -(3-(2-pyrrolidone)propyl)amide,

and salts, solvates or hydrates thereof.

Compounds of the invention which are presently especially preferred fortheir balance of good formulation characteristics such as watersolubility, high intrinsic activity in inhibiting collagenase andstromelysin, activity in inhibiting TNF release, and goodpharmacokinetic properties, evidenced for example by high in vivoactivity following oral administration in the standard rat adjuvantarthritis model, are:

N² - 3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹ methylamide;

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-tert-leucine-N.sup.1-methylamide,

and salts, solvates or hydrates thereof.

Compounds according to the present invention may be prepared by methodsknown per se in the art, and by the following process, which formsanother aspect of the invention, namely a process for the preparation ofa compound of formula (I) comprising:

(a) coupling an acid of general formula (II) ##STR3## or an activatedderivative thereof with hydroxylamine, O-protected hydroxylamine, or asalt thereof, R₂, R₃, R₄, and R₅ being as defined in general formula (I)except that any substituents in R₂, R₃, R₄, and R₅ which are potentiallyreactive with hydroxylamine, O-protected hydroxylamine or their saltsmay themselves be protected from such reaction, then removing anyprotecting groups from the resultant hydroxamic acid moiety and from anyprotected substituents in R₂, R₃, R₄, and R₅ ; and

(b) optionally convening a compound of general formula (I) into anothercompound of general formula (I).

Conversion of (II) to an activated intermediate such as thepentafluorophenyl, hydroxysuccinyl, or hydroxybenzotriazolyl ester maybe effected by reaction with the appropriate alcohol in the presence ofa dehydrating agent such as dicyclohexyl dicarbodiimide (DCC),N,N-dimethylaminopropyI-N'-ethyl carbodiimide (WSCDI), or2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ).

Protecting groups as referred to above are well known per se, forexample from the techniques of peptide chemistry. Amino groups are oftenprotectable by benzyloxycarbonyl, t-butoxycarbonyl or acetyl groups, orin the form of a phthalimido group. Hydroxy groups are often protectableas readily cleavable ethers such as the t-butyl or benzyl ether, or asreadily cleavable esters such as the acetate. Carboxy groups are oftenprotectable as readily cleavable esters, such as the t-butyl or benzylester.

A compound of general formula (II) can be prepared by coupling an acidof formula (III) or an activated derivative thereof with an amine offormula (IV) ##STR4## wherein R₂, R₃, R₄, and R₅ are as defined ingeneral formula (I) and R₁₀ and R₁₁ separately represent hydroxyprotecting groups or taken together represent a divalent moeity whichsimultaneously protects both hydroxy groups, and subsequently removingthe protecting groups or protecting moeity. Active derivatives of acids(III) include activated esters such as the pentafluorophenyl ester, acidanhydrides and acid halides, eg chlorides. R₁₀ and R₁₁ may be any of thestandard hydroxyl protecting groups known in the art, but a particularlyuseful technique may be simultaneous protection of the two hydroxygroups as a dioxalone of formula (V): ##STR5## wherein the groups R₁₂and R₁₃ are derived from a dioxalone forming reagent, and may be, forexample, hydrogen, alkyl, phenyl or substituted phenyl.

As mentioned above, compounds of formula (I) are useful in human orveterinary medicine since they are active as inhibitors of MMPs, and afurther advantage lies in their ability to inhibit the release of tumornecrosis factor (TNF) from cells.

Accordingly in another aspect, this invention concerns:

(i) a method of management (by which is meant treatment or prophylaxis)of diseases or conditions mediated by MMPs and/or TNF in mammals, inparticular in humans, which method comprises administering to the mammalan effective amount of a compound as defined with respect to formula (I)above, or a pharmaceutically acceptable salt thereof; and

(ii) a compound as defined with respect to formula (I) for use in humanor veterinary medicine, particularly in the management (by which ismeant treatment or prophylaxis) of diseases or conditions mediated byMMPs and/or TNF; and

(iii) the use of a compound as defined with respect to formula (I) inthe preparation of an agent for the management (by which is meanttreatment or prophylaxis) of diseases or conditions mediated by MMPsand/or TNF.

Diseases or conditions mediated by MMPs include those involving tissuebreakdown such as bone resorption, inflammatory diseases, dermatologicalconditions and tumor invasion by secondary metastases, in particularrheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, cornealulceration and tumor invasion by secondary metastases. Diseases orconditions mediated by TNF include inflammation, fever, cardiovasculareffects, haemorrhage, coagulation and acute phase response, cachexia andanorexia, acute infections, shock states, graft versus host reactionsand autoimmune disease.

In a further aspect of the invention there is provided a pharmaceuticalor veterinary composition comprising a compound of formula (I) togetherwith a pharmaceutically or veterinarily acceptable excipient or carrier.In view of the water-solubility, and oral bioavailability advantages ofcompounds in accordance with the invention, a further aspect of theinvention comprises a pharmaceutical or veterinary compositioncomprising a compound of formula (I) together with a pharmaceutically orveterinarily acceptable excipient or carrier, characterised in that thecomposition is adapted for oral administration.

One or more compounds of general formula (I) may be present in thecomposition together with one or more excipient or carrier.

The compounds with which the invention is concerned may be prepared foradministration by any route consistent with their pharmacokineticproperties. The orally administrable compositions may be in the form oftablets, capsules, powders, granules, lozenges, liquid or gelpreparations, such as oral, topical, or sterile parenteral solutions orsuspensions. Tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

The dosage unit involved in oral administration may contain from about 1to 250 mg, preferably from about 25 to 250 mg of a compound of theinvention. A suitable daily dose for a mammal may vary widely dependingon the condition of the patient. However, a dose of a compound ofgeneral formula I of about 0.1 to 300 mg/kg body weight, particularlyfrom about 1 to 100 mg/kg body weight may be appropriate.

For topical application to the skin, the drug may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

For topical application to the eye, the drug may be made up into asolution or suspension in a suitable sterile aqueous or non aqueousvehicle. Additives, for instance buffers such as sodium metabisulphiteos disodium edeate; preservatives including bactericidal and fungicidalagents such as phenyl mercuric acetate or nitrate, benzalkonium chlorideor chlorhexidine, and thickening agents such as hypromellose may also beincluded.

The dosage for topical administration will of course depend on the sizeof the area being treated. For the eyes, each dose may typically be inthe range from 10 to 100 mg of the drug.

The active ingredient may also be administered parenterally in a sterilemedium. Depending on the vehicle and concentration used, the drug caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as a local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle.

For use in the treatment of rheumatoid arthritis, the drug can beadministered by the oral route or by injection intra-articularly intothe affected joint. The daily dosage for a 70 kg mammal may be in therange 10 mgs to 1 gram.

The following Examples illustrate embodiments of the invention:

The amino acids used in the examples below were commercially availableor were prepared according to literature procedures. In all cases thesewere converted to the required N-methylamides by standard methods.

EXAMPLE 1

N² - 3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹ methylamide ##STR6##

EXAMPLE 1a

Isopropyl 3R-carboxyisopropyl-2S-hydroxy-5-methylhex-5-enoate

Diisopropyl-2S-hydroxybutanedioate (50 g, 230 mmol) was added to asolution of lithium N,N-diisopropylamide from N,N-diisopropylamine (80ml, 570 mmol) and 10M n-butyllithium (48.1 ml, 481 mmol)! in drytetrahydrofuran (500 ml) whilst maintaining the temperature at -70° C.When addition was complete the reaction was warmed to -15° C. andstirred for 8 hours. The reaction mixture was cooled to -70° C. andmethallyl iodide (46 g, 252 mmol) was added slowly, ensuring that thetemperature did not exceed -65° C. The mixture was warmed to -40° C. andstirred for 18 hours before quenching at -15° C. with citric acid. Theorganic layer was separated and washed with 10% sodium bicarbonatesolution (500 ml) and brine (300 ml) then dried over magnesium sulphate.The solution was filtered and concentrated in vacuo to give a brown oil(64 g) which was purified by column chromatography (silica gel, 1 kg,gradient elution with 20 to 35% diethyl ether in hexane). The desiredproduct was isolated as a colourless oil (30.9 g, 49%) which was foundto be a 17:1 mixture of diastereomers by NMR. ¹ H-NMR; δ (Chloroform-d,major diastereomer), 5.06 (1H, septet, J=6.3 Hz), 4.97 (1H, septet,J=6.3 Hz), 4.78 (2H, d, J=7.1 Hz), 4.16 (1H, m), 3.20 (1 H, d, J=6.2Hz), 3.00 (1H, m), 2.50, 2.35 (2H, ABX, J=7.0, 8.7, 14.4 Hz), 1.72 (3H,s) and 1.24-1.16 (12H, 2m).

EXAMPLE 1b

Isopropyl 3R-carboxyisopropyl-2S-hydroxy-5-methylhexanoate

Isopropyl 3R-carboxyisopropyl-2S-hydroxy-5-methylhex-5-enoate (7.14 g,26.2 mmol) was dissolved in ethanol (80 ml), and stirred overnight with10% palladium on charcoal catalyst (1.0 g) under an atmosphere ofhydrogen. The catalyst was removed by filtration and the filtrate wasevaporated to dryness to leave the product as a clear oil (7.03 g, 98%).¹ H-NMR; δ (Chloroform-d), 5.06 (1 H, septet, J=6.3 Hz), 4.97 (1H,septet, J=6.3 Hz), 4.17 (1H, brs,), 3.24 (1H, brs), 2.83 (1H, m), 1.68(2H, m), 1.44 (1H, m), 1.24 (6H, d, J=6.2 Hz), 1.18 (6H, d, J=6.2 Hz)and 0.89 (6H, m).

EXAMPLE 1c

3R-Carboxy-2S-hydroxy-5-methylhexanoic acid

Isopropyl 3R-Carboxyisopropyl-2S-hydroxy-5-methylhexanoate (7.0 g, 25.6mmol) was dissolved in dioxane (15 ml) and water (15 ml), a solution ofpotassium hydroxide (4.29 g) in water (22 ml) was added and the mixturewas heated at 90° C. overnight. The solution was allowed to cool andthen passed through an ion exchange resin (Dowex 50X4-400, 200 ml) toyield the title compound (4.82 g, 99%). ¹ H-NMR; δ (Chloroform-d), 8.70(2H, br s), 4.32 (1H, br s), 3.10 (1H, m), 1.8-1.55 (3H, m) and 0.96(6H, m).

EXAMPLE 1d

2R-(2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl)-4-methylpentanoic acid

3R-Carboxy-2S-hydroxy-5-methylhexanoic acid (5.19 g, 27.3 mmol) wasdissolved in 2,2-dimethoxypropane (150 ml) and N,N-dimethylformamide (40ml) and stirred overnight at 30° C. in the presence of a catalyticamount of p-toluene sulphonic acid. The solvent was removed to give thetitle compound contaminated with solvent (6.87 g, >100%). ¹ H-NMR; δ(Chloroform-d), 4.41 (1 H, d, J=4.8 Hz), 2.91 (1H, m), 1.69 (3H, m),1.54 (3H, s), 1.48 (3H, s) and 0.88 (6H, m).

EXAMPLE 1e

Pentafluorophenyl R-(2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl)-4-methylpentanoate

2R-(2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl)-4-methylpentanoic acid (558mg, 2.4 mmol) was taken up in dichloromethane (10 ml) and cooled to 0°C. before adding pentafluorophenyl (670 mg, 3.6 mmol) andN-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (560 mg, 2.9 mmol). Thereaction was stirred at 0° C. for 2 hours then the solution was washedwith 1M sodium carbonate (50 ml) and brine (20 ml). The organic layerwas dried (magnesium sulphate), filtered, evaporated to dryness andpurified by column chromatography (silica gel, dichloromethane) to givethe activated ester (552 mg, 58%). ¹ H-NMR; δ (Chloroform-d), 4.57 (1H,d, J=6.5 Hz), 3.32 (1H, m), 1.86 (3H, m), 1.67 (3H, s), 1.58 (3H, s) and1.03 (6H, m).

EXAMPLE 1f

N² -2R-(2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl)-4-methylpentanoyl!-L-cyclohexylalanine-N¹ -methylamide

Pentafluorophenyl 2R-(2,2-dimethyl-4-oxo-1,3-dioxalan-5S-yl)-4-methylpentanoate (1.06 g, 2.7 mmol) and L-cyclohexylalanine-N-methylamide(0.33 g, 1.8 mmol) were dissolved in N,N-dimethylformamide (150 ml) andthe mixture was stirred overnight at room temperature. The solvent wasremoved to give an oil which was purified by column chromatography(silica gel, gradient elution with 0 to 5% methanol in dichloromethane)gave first unreacted ester followed by the desired product (0.43 g,60%). ¹ H-NMR; δ (Chloroform-d), 6.47 (2H, br m and d, J=8.3 Hz), 4.53(1 H, d, J=6 Hz), 4.49 (1 H, m), 2.76 (4H, m), 1.80-1.50 (12H, br m),1.62 (3H, s), 1.54 (3H, s), 1.35-1.10 (4H, br m) and 0.91 (6H, m).

EXAMPLE 1g

N² - 3S-Hydroxy-4-hydroxy-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹-methylamide

N² -2R-(2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl)-4-methylpentanoyl!-L-cyclohexylalanine-N¹ -methylamide (0.43 g, 1.1 mmol) was dissolved in 2Mhydrochloric acid (15 ml) and tetrahydrofuran (20 ml) and stirred atroom temperature overnight. The solvent was removed to give the requiredproduct as an off white foam (0.35 g, 91%). ¹ H-NMR; δ (Methanol-d₄),4.37 (1H, m), 4.16 (1H, d, J=5.6 Hz), 2.75 (1H, m), 2.68 (3H, s),1.80-1.50 (12H, m), 1.38-1.10 (4H, br m) and 0.90 (6H, m).

EXAMPLE 1h

N² -4-(N-Benzyloxyamino)-3S-hydroxy-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹-methylamide

N² - 3S-Hydroxy-4- hydroxy-2R-isobutylsuccinyl)!-L-cyclohexylalanine-N¹-methylamide (0.35 g, 1.0 mmol) was taken up in tetrahydrofuran (5 ml)then water (5 ml) and 0-benzylhydroxylamine hydrochloride (0.24 g, 1.5mmol) was added. The solution was cooled to 0° C. before addition ofN-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g,2.0 mmol) and the reaction mixture was then stirred at room temperatureovernight. Tetrahydrofuran was removed under reduced pressure, whereuponthe product crystallised. The mixture was diluted with an equal volumeof water and the product was collected by filtration, washed with waterand dried under high vaccuum (0.30 g, 65%). ¹ H-NMR; δ (Methanol-d₄),7.50-7.30 (5H, m), 4.81 (2H, s; under H₂ O peak), 4.36 (1H, t, J=7.6Hz), 3.98 (1H, d, J=6.1 Hz), 2.72 (1H, m), 2.67 (3H, s), 1.85-1.43 (12H,br m), 1.38-1.10 (4H, br m) and 0.88 (6H, m).

EXAMPLE 1i

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cylohexylalanine-N.sup.1-methylamide

N² -4-(N-Benzyloxyamino)-2S-hydroxy-2R-isobutylsuccinyl)!-L-cyclohexylalanine-N¹-methylamide (1.0 g, 2.16 mmol) was dissolved in ethanol (100 ml), 10%palladium on charcoal (100 mg) was added and the mixture was subjectedto an atmosphere of hydrogen. After 4 hours the catalyst was filteredoff then the solvent removed to give the title compound (650 mg, 1.75mmol, 81%): ¹ H-NMR; δ (Methanol-d₄), 4.35 (1H, t, J=7.6 Hz), 3.99 (1 H,d, J=6.4 Hz), 2.69 (4H, m and s), 1.80-1.50 (12H, br m), 1.40-1.10 (4H,br m) and 0.89 (6H, m). ¹³ C-NMR; δ (Methanol-d₄), 175.6, 175.3, 171.5,72.9, 52.4, 40.2, 39.2, 35.2, 34.9, 33.2, 30.9, 27.6, 27.4, 27.1, 26.9,26.3, 23.7 and 22.1. Found: C, 58.27, H, 8.93, N, 11.20%; C₁₈ H₃₃ N₃ O₅requires: C, 58.20, H, 8.95, N, 11.31%.

EXAMPLE 2

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-oxymethylcarboxy)phenylalanine-N¹ -methylamide ##STR7##

EXAMPLE 2a

Methyl 3R-carboxy-2S-hydroxy-5-methylhexanoate

3R-Carboxy-2S-hydroxy-5-methylhexanoic acid (5.76 g, 30.3 mmol),prepared by the method described in Example 1c, was cooled to 0° C. andtreated with trifluoroacetic anhydride (14 ml). The mixture was stirredfor 2 hours then the excess anhydride was removed under reducedpressure. The resulting brown oil was dissolved in freshly distilledanhydrous methanol (30 ml) and stirred overnight. The solution wasevaporated to give the crude product (7.0 g, >100%) which was usedwithout further purification. ¹ H-NMR; δ (Chloroform-d), 4.28 (1H, d,J=6 Hz), 3.80 (3H, s), 3.00 (1H, dt, J=6, 8 Hz), 1.73 (2H, m), 1.54 (1H,m), and 0.96 (6H, m). ¹³ C-NMR; δ (Chloroform-d), 176.2, 172.5, 69.6,51.3, 45.0, 35.3, 24.2, and 20.9.

EXAMPLE 2b

N² - 3S-Hydroxy-2R-isobutyl-4-methoxysuccinyl!-L-(4-oxymethylcarboxybenzyl)phenylalanine-N¹ -methylamide

Methyl 3R-carboxy-2S-hydroxy-5-methylhexanoate (700 mg, 3.4 mmol),4-(oxy methylcarboxybenzyl)-L-phenylalanine-N-methylamide (1.56 g, 4.56mmol), pentafluorophenol (1.26 g, 6.8 mmol) and N-methylmorpholine (690mg, 6.8 mmol) were dissolved in dimethylformamide (30 ml) and cooled to0° C. before addition of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimidehydrochloride (980 mg, 5.1 mmol). After stirring overnight at roomtemperature the solvent was removed under reduced pressure and theresidue was purified by column chromatography (C30 silica gel, gradientelution with 50 to 100% ethyl acetate in hexane). The desired productwas isolated as a pale yellow solid (1.42 g, 78%). ¹ H-NMR; δ(Chloroform d), 7.34 (5H, s), 7.09 (2H, d, J=8 Hz), 6.92 (1H, d, J=8Hz), 6.79 (2H, d, J=8 Hz), 6.55 (1H, q, J=6 Hz), 5.20 (2H, s), 4.60 (3H,m), 4.22 (1H, d, J=4 Hz), 3.71 (3H, s), 3.00 (2H, m), 2.76 (1H, m), 2.48(3H, d, J =6 Hz), 1.55 (1H, m), 1.42 (2H, m), 0.88 (3H, d, J=7 Hz), and0.88 (3H, d, J=7 Hz). ¹³ C-NMR; δ (Chloroform-d), 172.6, 172.3, 171.7,170.3, 134.3, 127.1, 126.9, 127.8, 70.4, 65.1, 51.0, 50.8, 46.1, 36.6,28.9, 26.2, 24.8, 24.2, 21.1, and 21.0.

EXAMPLE 2c

N² -4-(N-Benzyloxyamino)-3S-hydroxy-2R-isobutylsuccinyl!-L-(4-oxymethylcarboxybenzyl)phenylalanine-N¹ -methylamide

N² -3S-Hydroxy-2R-isobutyl-4-methoxysuccinyl!-L-(4-oxymethylcarboxybenzyl)phenylalanine-N¹ -methylamide (820 mg, 1.55 mmol) was dissolved intetrahydrofuran (7 ml) and water (7 ml), lithium hydroxide (66 mg, 1.55mmol) was added and the solution was stirred overnight at ambienttemperature. Evaporation of the solvents under reduced pressure gave thecarboxylic acid lithium salt which was characterised by ¹ H NMR. Thesalt was redissolved in tetrahydrofuran (15 ml) and water (15 ml) andtreated with O-benzylhydroxylamine hydrochloride (0.30 g, 1.86 mmol)followed by N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.36 g, 1.86 mmol). After stirring overnight at room temperature thetetrahydrofuran was removed to leave an oil which was extracted severaltimes with ethyl acetate. The combined organic solutions were dried(magnesium sulphate), filtered and concentrated. Further purification bycolumn chromatography (C30 silica gel, ethyl acetate) gave the titlecompound as a white solid (213 mg, 22%). ¹ H-NMR; δ (Methanol-d₄), 7.80(1H, d, J=8 Hz), 7.41 (2H, m), 7.32 (8H, m), 7.19 (2H, d, J=8 Hz), 6.78(2H, d, J=8 Hz), 5.17 (2H, s), 4.80 (4H, m), 4.50 (1H, dd, J=7, 8 Hz),3.99 (1H, d, J=4 Hz), 3.07 (1H, dd, J=14, 6 Hz), 2.88 (1H, dd, J=14, 8Hz), 2.64 (4H, m and s), 1.46 (1H, m), 1.29 (1H, m), 1.12 (1H, m), and0.80 (6H, t, J=7 Hz).

EXAMPLE 2d

N² - 3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-oxymethylcarboxy)phenylalanine-N'-methylamide

N² -4-(N-Benzyloxyamino)-3S-hydroxy-2R-isobutylsuccinyl!-L-(4-oxymethylcarboxybenzyl)phenylalanine-N¹ -methylamide (210 mg, 0.34 mmol) was dissolvedin ethanol (35 ml) and hydrogenated over 10% palladium on charcoal (200mg) for one hour. The catalyst was removed by filtration and the solventwas removed to give the desired compound (140 mg, 93%): ¹ H-NMR; δ(Methanol-d₄), 7.1 (2H, d, J=8.5 Hz), 6.8 (2H, d, J=8.5 Hz), 4.5 (2H,s), 4.4 (1H, dd, J=8.2, 6.7 Hz), 4.01 (1H, d, J=5.6 Hz), 3.05 (2H, dd,J=l 2.9, 6.2 Hz), 2.90 (2H, dd, J=l 3.9, 8.3 Hz), 2.61 (1H, m), 2.60(3H, s), 1.3 (3H, m), and 0.8 (6H, t, J=6.3 Hz). ¹³ C-NMR; δ(Methanol-d₄), 175.5, 173.9, 171.5, 158.5, 131.3, 131.1, 115.7, 72.7,66.7, 58.3, 56.3, 39.3, 37.9, 26.6, 26.4, 23.8, 22.1, and 18.4.

EXAMPLE 3

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-phenylglycine-N.sup.1-methylamide ##STR8## Prepared in a manner analogous to that describedin example 1, from L-phenylglycine-N-methylamide. ¹ H-NMR; δ(Methanol-d₄), 7.37 (5H, m), 5.4 (1H, s), 4.05 (1H, d, J=5 Hz), 3.1 (1H,m), 2.7 (3H, s), 1.6 (2H, m), 1.27 (1H, m), 0.9 (6H, 2d, J=6 Hz). ¹³C-NMR; δ (Methanol-d₄), 175.3, 172.9, 171.5, 139.0, 129.7, 129.1, 128.5,73.0, 58.7, 43.4, 39.1, 26.8, 26.5, 23.6, 22.3.

EXAMPLE 4

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-phenyl)-phenylalanine-N¹-methylamide ##STR9## Prepared in a manner analogous to that describedin Example 1, from L-(4-phenyl) phenylalanine-N-methylamide: ¹ H-NMR; δ(Dimethyl sulphoxide-d₆), 7.90 (2H, m), 7.62 (2H, d, J=7.9 Hz), 7.46(6H, m), 7.30 (2H, d, J=7.9 Hz), 5.66 (1H, br s), 4.44 (1H,m), 3.86 (1H,d, J=6.9 Hz), 3.12 (1H, dd, J=5.2, 13.8 Hz), 2.93 (1H, dd, J=9.1, 13.8Hz), 2.58 (3H, d, J=4.3 Hz), 2.51 (1H, m), 1.40 (1H, m), 1.24 (1H, m)1.19 (1H, br m), 0.94 (1H, m) and 0.72 (6H, m). ¹³ C-NMR; δ (Dimethylsulphoxide-d₆), 172.5, 171.1, 168.7, 140.1, 138.0, 137.5, 129.6, 128.9,127.2, 126.4, 126.3, 71.2, 54.1, 48.3, 37.4, 36.6, 25.6, 25.0, 23.6 and21.5. Found: C, 63.43, H, 7.00, N, 8.92%; C₂₄ H₃₁ N₃ O₅.0.7H₂ Orequires: C, 63.48, H, 7.19, N, 9.25%.

EXAMPLE 5

N³ -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!amino-1-azacyclotridecan-2-one##STR10## Prepared in a manner analogous to that described in Example 1,from 3(RS)-amino-1 azacyclotridecan-2-one: ¹ H-NMR; δ (Dimethylsulphoxide-d₆), 10.60 (1H, d, J=10.7 Hz), 8.86 (1H, d, J=7.9 Hz), 7.83(1H, d, J=7.3 Hz), 7.61 (1H, d, J=7.6 Hz), 5.46 (0.5 H, d, J=6.4 Hz;diastereomer A), 5.31 (0.5 H, d, J =7.5 Hz; diastereoisomer B), 4.22(1H, m), 3.72 (1H, d, J=7.4 Hz), 2.98 (1H, br m), 2.78 (2H, br m),1.6-1.25 (21H, br m) and 0.82 (6H, m). ¹³ C-NMR; δ (Dimethylsulphoxide-d₆), 175.5, 173.9, 171.5, 73.4, 55.4, 54.9, 40.0, 39.5, 39.0,32.7, 29.3, 27.7, 27.1, 26.8, 26.1, 25.4, 24.6, 23.6, 23.0 and 22.3.

EXAMPLE 6

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(1-pyrazolyl)alanine-N¹ -methylamide ##STR11## Prepared in a manner analogous to thatdescribed in Example 1, from L-3-(1H pyrazolyl)alanine-N-methylamide. ¹H-NMR; δ (Dimethyl sulphoxide-d₆), 10.70 (1H, s), 8.93 (1H, s), 8.00(2H, m), 7.59 (1H, d, J=2 Hz), 7.41 (1H, d, J=1.5 Hz), 6.22 (1H, m),5.75 (1H, d, J=5.8 Hz), 4.57 (t H, m), 4.46 (2H, m), 3.86 (1H, dd, J=6.2Hz), 2.55 (4H, m), 1.44 (1H, m), 1.25 (1H, m), 0.97 (1H, m) and 0.76(6H, m). ¹³ C-NMR; δ (Dimethyl sulphoxide-d₆), 172.7, 169.2, 168.6,138.9, 130.6, 104.9, 71.1, 53.6, 51.6, 48.4, 37.1, 25.7, 25.0, 23.6 and21.5. Found: C, 50.11, H, 7.01, N, 8.92%; C₁₅ H₂₅ N₅ O₅.0.2H₂ Orequires: C, 50.19, H, 7.13, N, 19.51%.

EXAMPLE 7

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-4-(N-hydroxyamino)glutamicacid-N¹ -methylamide ##STR12## Prepared in a manner analogous to thatdescribed in Example 1, from 5-methyl-L glutamic acid N-methylamide. ¹H-NMR; δ (Dimethyl sulphoxide-d₆), 10.64 (1H, br s), 10.30 (1H, br s),8.9 (1H, br s), 8.7 (1H, br s), 7.8 (1H, d, J=8 Hz), 7.72 (1H, d, J=4.5Hz), 5.35 (1H, d, J=6.9 Hz), 4.16 (1H, m), 3.75 (1H, m), 2.57 (4H, d andm), 2.14-1.73 (4H, br m), 1.44 (3H, br m), and 0.80 (6H, m). ¹³ C-NMR; δ(Dimethyl sulphoxide-d₆), 172.8, 171.4, 168.7, 168.6, 71.3, 52.3, 47.7,37.2, 28.9, 28.0, 25.5, 25.2, 23.6 and 21.7.

EXAMPLE 8

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(2-thienyl)alanine-N¹-methylamide ##STR13## Prepared in a manner analogous to that describedin Example 1, from L-3-(2 thienyl)alanine-N-methylamide. ¹ H-NMR; δ(Methanol-d₄), 7.18 (1H, d, J=4.8 Hz), 6.88 (2H, dd, J=3.5, 4.8 Hz),4.49 (1H, dd, J=7.0 Hz), 4.01 (1H, d, J=5.4 Hz), 3.27 (2H, m), 2.67 (4H,m), 1.53 (1H, m), 1.33 (1H, m), 1.24 (1H, m) and 0.82 (6H, m). ¹³ C-NMR;δ (Methanol-d₄), 175.6, 173.3, 1 71.4, 140.2, 127.8, 127.5, 125.3, 72.7,56.2, 39.2, 32.6, 26.6, 26.4, 23.7, 22.1 and 21.9.

EXAMPLE 9

N² - 3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹ -(3-(2-pyrrolidone)propyl)amide ##STR14## Prepared in amanner analogous to that described in Example 1, fromL-cyclohexylalanine-N-(3-(2-pyrrolidone)propyl)amide: ¹ H-NMR; δ(Methanol-d₄), 4.35 (1H, m), 4.01 (1H, d, J=6.3 Hz), 3.43 (2H, m), 3.27(2H, m), 3.15 (2H, m), 2.73 (1H, m), 2.34 (2H, t, J=7.8 Hz), 2.01 (2H,m), 1.70 (15H, br m), 1.21 (3H, br m) and 0.90 (6H, dd, J=5.3, 6.3 Hz).¹³ C-NMR; δ (Methanol-d₄), 177.9, 175.7, 174.8, 171.5, 73.0, 52.7, 41.2,40.3, 39.3, 37.8, 35.4, 34.9, 33.2, 32.0, 27.8, 27.6, 27.4, 27.1, 26.9,23.8, 22.3 and 18.9. Found: C, 60.06, H, 8.88, N, 11.60%; C₂₄ H₄₂ N₄ O₆requires: C, 59.73, H, 8.77, N, 11.61%.

EXAMPLE 10

N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-tert-leucine-N.sup.1-methylamide ##STR15## Prepared in a manner analogous to that describedin Example 1, from L-tert-leucine-N methylamide: ¹ H-NMR; δ(Methanol-d₄), 4.17 (1H, s), 4.00 (1H, d, J=5.6 Hz), 2.81 (1H, m), 2.69(3H, s), 1.65-1.44 (2H, br m), 1.29-1.21 (1H, br m), 0.95 (9H, s), 0.88(3H, d, J=6.5 Hz) and 0.86 (3H, d, J=6.5 Hz). ¹³ C-NMR; δ (Methanol-d₄),175.4, 173.2, 171.5, 73.0, 62.1, 39.8, 35.4, 27.2, 26.9, 26.0, 23.5 and22.4. Found: C, 54.36, H, 8.74, N, 12.73% ; C₁₅ H₂₉ N² O₅ requires: C,54.36, H, 8.82, N, 12.68%.

Biological Example A

The potency of compounds of the invention as inhibitors of collagenasewas determined by the procedure of Cawston and Barrett, (Anal. Biochem.,99, 340-345, 1979), hereby incorporated by reference, whereby a 1 mMsolution of the compound being tested, or a dilution thereof, wasincubated at 37° for 16 hours with collagen and collagenase (bufferedwith 25 mM Hepes, pH 7.5 containing 5 mM CaCl₂, 0.05% Brij 35 and 0.02%NaN₃). The collagen was acetylated ¹⁴ C collagen prepared by the methodof Cawston and Murphy, (Methods in Enzymology, 80, 711, 1981), herebyincorporated by reference. The samples were centrifuged to sedimentundigested collagen, and an aliquot of the radioactive supernatantremoved for assay on a scintillation counter as a measure of hydrolysis.The collagenase activity in the presence of 1 mM of the test compound,or a dilution thereof, was compared to activity in a control devoid ofinhibitor and the result reported below as that of inhibitorconcentration effecting 50% inhibition of the collagenase activity(IC₅₀).

The potency of compounds of the invention as inhibitors of stromelysinwas determined by the procedure of Cawston et al, (Biochem. J.,195,159-165, 1981), hereby incorporated by reference, whereby a 1 mMsolution of the compound being tested, or a dilution thereof, wasincubated at 37° for 16 hours with stromelysin and ¹⁴ C acetylate casein(buffered with 25 mM Hepes, pH 7.5 containing 5 mM CaCl₂, 0.05% Brij 35and 0.02% NaN₃). The casein was acetylated ¹⁴ C casein prepared by themethod of Cawston et al (ibid). The stromelysin activity in the presenceof 1 mM of the test compound, or a dilution thereof, was compared toactivity in a control devoid of inhibitor and the result reported belowas that of inhibitor concentration effecting 50% inhibition of thestromelysin activity (IC₅₀).

In the following results the potencies of the compounds of examples 1-10above in the above tests are compared in the same tests with theproducts of examples 13 and 27 of EP-A-236872 (Roche), namely:

4-(N-hydroxyamino) 2(R)-isobutylsuccinyl)!-L-leucyl-L-alanine ethylester, and

4-(N-hydroxyamino)3(S)-phthaloylaminobutyl-2(R)-isobutyisuccinyl)!-L-leucyl glycyl ethylester.

The former compound (hereafter referred to as C1) was chosen forcomparison because of the collagenase inhibitors whose activity isreported in EP-A-236872, it is the most active. The latter compound(hereafter referred to as C2) was chosen for comparison because of thecollagenase inhibitors whose activity is reported in EP-A-236872, it isthe only one with a substituent in the position equivalent to thehydroxy substituent of the compounds of this invention.

    ______________________________________                                        Results:                                                                      Compound     Collagenase IC50                                                                          Stromelysin IC50                                     ______________________________________                                        Example 1     5           60                                                  Example 2    30          200                                                  Example 3    100         not done                                             Example 4    10          not done                                             Example 5    20          not done                                             Example 6    30          3000                                                 Example 7    150         500                                                  Example 8    10          100                                                  Example 9    30          not done                                             Example 10    8          200                                                  C1           15          300                                                  C2            7           70                                                  ______________________________________                                    

Biological Example B

The concentration over time of compounds of the invention in the bloodof laboratory animals following administration of the test compounds wasmeasured.

Test compounds were administered by gavage to 6 male rats (300 g) pertreatment group. Blood samples were removed by tail venepuncture at 0.5,1.0, 2.0, 6.0 and 24 hours post administration. 0.4 ml of blood wasplaced into 4.5 ml tubes containing 0.1 ml acid citrate dextrose (ACD)as anti-coagulant. For extraction, 3 ml methanol was added and theprecipitated blood pelletted by centrifugation (30 min at 3000 rpm). A 2ml aliquot of supernatant was removed and concentrated bylyophilisation. The extract was redissolved in 200 μl DMSO and a 10 μlaliquot assayed for collagenase inhibitory activity. The inhibitoryactivity in the extracts was determined using the collagenase assaydescribed in Biological Example A above, and the concentration ofinhibitor (that is drug plus any active metabolites) obtained bycomparison with standard curves. Results are expressed as peakconcentration in ng/ml, as area under the curve (AUC) in ng/ml×hours,over 0-6 hours, and as AUC in number of IC₅₀ 's×hours.

The compound of examples 1 and 10 above were compared with thecomparison compounds C1 and C2.

    ______________________________________                                        Results                                                                                              AUC (0-6 h)                                                                             AUC (0-6 h)                                  Compound                                                                              Peak con. ng/ml                                                                              ng/ml × h                                                                         n IC.sub.50 's × h                     ______________________________________                                        Example 1*                                                                             59 @ 0.5 h    143.25    46.2                                         Example 10                                                                            139 @ 0.5 h    343       190                                          C1       25 @ 0.5 h    91.7      7.4                                          C2       1 @ 1 h       5.3       2.12                                         ______________________________________                                         *average of two results                                                  

Biological Example C

The activities of the compound of example 1 above and comparisoncompound C1 (see Biological Example A above) were assessed in anadjuvant-induced arthritis model.

Adjuvant arthritis was produced in male Lewis rats (Charles River) by asingle intradermal injection of 0.75 mg of M. butyricum in lightparaffin oil (Freunds complete adjuvant--FCA) into the base of the tail.The "secondary" lesion occurs after a delay of 10 days, and ischaracterised by inflammation of the hindpaws. Hindpaw edemia volumeswere measured plethysmographically by water displacement. The testcompound was dosed b.i.d. from days 13 to 17. Paw volume on day 20 wasmeasured and compared to that on day 13. The experiment was terminatedon day 23.

On day 20, the compound of example 1 (dosed at 10 mg/kg) showed astatistically significant (p<0.01) reduction in swelling relative tocontrol, whereas compound C1 had no effect.

Biological Example D

The compound of example 1 above was tested for activity in vivo in a ratmammary carcinoma model. A lung colonisation assay was performed inorder to determine whether the compound of example 1 above is effectivein inhibiting lung colonisation by circulating HOSP1.P mammary carcinomacells after oral administration.

HOSP1.P cells (1×10⁵ cells/animal) were administered to two groups of 12rats by injection into the jugular vein. The product of example 1 wasadministered p.o. to one group at 30 mg/kg at -4, +1, +6, +24 and +72hours relative to tumor cell inoculation at 0 hours. The second(control) group received only vehicle (p.o.) by the same schedule.Animals were killed after 34 days. Lungs were removed and individualtumors counted after 24 hours fixation in Methacarn. No extrapulmonarytumors were found. Treatment with the product of example 1 resulted in asignificant inhibition of lung colonisation relative to the controlgroup. (p<0.01, Mann-Whitney, two tailed).

    ______________________________________                                        Results:                                                                      Lung Colony Number:                                                           Group   Mean      Standard Deviation                                                                          Median p                                      ______________________________________                                        Control 70.50     27.74         71.50  --                                     Treated 38.91     12.49         38.50  <0.01                                  ______________________________________                                    

Biological Example E

The ability of compounds of the invention to inhibit the release of TNFwas investigated. The assay is based on the ability of phorbol myristateacetate (PMA) to stimulate the release of TNF α from a human monocyticcell line, U937.

U937 cells cultured in RPMI 1640 medium+5% foetal calf serum arecentifuged at 1000×g for 5 minutes and then resuspended in medium at2×10⁶ /ml. 1 ml of cell suspension is aliquoted into individual wells of24-well plates. Test compounds are dissolved in dimethyl sulphoxide(DMSO) at a stock concentration of 100 mM, then diluted to 50× the finalrequired concentration with RPMI 1640 medium. 20 μl of the dilutedcompounds are added to U937 cells in duplicate wells. TNF α release isstimulated by addition of PMA to the cells at a final concentration of50 nM. Appropriate control cultures are set up in duplicate. The platesare incubated for 18 hours at 37° C., 5% CO₂, then centrifuged at 1000×gfor 5 minutes. A specific ELISA for TNF α obtained from BritishBio-technology Products Limited, Abingdon, England is used to measureTNF α levels in the culture supernatants.

The average concentration of test compound which inhibits the release ofTNF α by 50% relative to the control culture was assessed. The compoundsof examples 1,2, 5 and 10 above were tested and had IC₅₀ values lessthan 50 μM.

Aqueous Solubility Example

The solubilities of compounds of the invention in water at ambienttemperature were measured, and compared with comparison compounds C1 andC2 (identified in Biological Example A above).

    ______________________________________                                        Results:                                                                      Compound      Solubility mg/ml                                                ______________________________________                                        Example 1     0.1                                                             Example 2     13.13                                                           Example 3     2.34                                                            Example 4     0.11                                                            Example 5     0.14                                                            Example 6     0.33                                                            Example 7     0.18                                                            Example 9     1.8                                                             Example 10    1.4                                                             C1            0.3                                                             C2            <0.1                                                            ______________________________________                                    

We claim:
 1. A compound of the formula (I): ##STR16## or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinR₂represents a group R₆ --A-- wherein A represents a divalent straight orbranched, saturated or unsaturated hydrocarbon chain of up to 6 carbonatoms or said chain interrupted by an O or S atom, and R₆ representshydrogen or an optionally substituted phenyl, C₃ -C₈ cycloalkyl or C₃-C₈ cycloalkenyl group; R₃ represents a group R₇ --(B)_(n) -- wherein nis 0 or 1, B represents a divalent straight or branched, saturated orunsaturated hydrocarbon chain of up to 6 carbon atoms or said chaininterrupted by an O or S atom, and R₇ is --CONHOH, carboxyl, esterifiedor antidated carboxyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl,heterocyclyl, phenyl, napthyl, or substituted phenyl or napthyl in whichthe substituent(s) are selected from the group consisting of phenyl,hydroxy, C₁ -C₆ alkoxy, benzyloxy, trifluoromethyl, halo and R₈--(C═O)--(C₁ -C₆ alkyl)--O-- wherein R₈ is hydroxy, amino, or an aminoacid residue linked via an amide bond; or (except when n=0) R₇ ishydrogen; R₄ represents hydrogen or methyl; R₅ represents hydrogen; C₁-C₆ alkyl; or a group D-(C₁ -C₆ alkyl) wherein D represents hydroxy, (C₁-C₆) alkoxy, (C₁ -C₆) alkylthio, acylamino, optionally substitutedphenyl, or a heterocyclic group, NH₂, or mono- or di-(C₁ -C₆ alkyl)amino; or R₃ and R₅ taken together represent a divalent, saturated orunsaturated hydrocarbon chain of from 8-14 carbon atoms, or said chaininterrupted by an O, S or N heteroatom; provided that R₃ is not thecharacteristic side chain of a natural alpha-amino acid, or thecharacteristic side chain of a natural alpha-amino acid in which anyfunctional substituents are protected, any amino groups are acylated,and any carboxyl groups are esterified.
 2. A compound as claimed inclaim 1, wherein the stereochemistry of said compound is as follows:thecarbon atom carrying the hydroxy group and hydroxamic acid moiety --S,the carbon atom carrying the R₂ group --R, the carbon atom carrying theR₃ group --S.
 3. A compound as claimed in claim 1 or claim 2, wherein R₂represents C₃ -C₆ alkyl, cycloalkyl(C₃ -C₆ alkyl), phenyl(C₂ -C₆ alkyl),C₂ -C₄ alkoxy(C₁ -C₃ alkyl, or C₂ -C₄ alkylsulphanyl(C₁ -C₃ alkyl).
 4. Acompound as claimed in claim 3, wherein R₂ represents isobutyl.
 5. Acompound as claimed in claim 1 or claim 2, wherein R₃ represents phenyl,C₁ -C₆ alkyl, C₂ -C₆ alkenyl, phenyl(C₁ -C₆ alkyl), substitutedphenyl(C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl(C₁ -C₆ alkyl),thienyl, thienyl(C₁ -C₆ alkyl), pyridyl(C₁ -C₆ alkyl), thiazolyl(C₁ -C₆alkyl), thiofuranyl(C₁ -C₆ alkyl), benzothiofuranyl(C₁ -C₆ alkyl) orimidazolyl(C₁ -C₆ alkyl), or R₃ and R₅ taken together may form a C₇ -C₁₂alkylene chain, or said alkylene chain interrupted by an O, S or Nheteroatom.
 6. A compound as claimed in claim 5, wherein R₃ representsphenyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, optionallysubstituted phenylethyl, phenylpropyl, phenylbutyl or phenylpentyl inwhich the optional substituent(s) are in the phenyl ring and areselected from the group consisting of phenyl, hydroxy, C₁ -C₆ alkoxy,benzyloxy, trifluoromethyl, halo and R₈ --(C═O)--(C₁ -C₆alkyl)--O--wherein R₈ is hydroxy, amino, or an amino acid residue linkedvia an amide bond.
 7. A compound as claimed in claim 5, wherein R₃ ist-butyl.
 8. A compound as claimed in claim 5 wherein R₃ iscyclohexylmethyl.
 9. A compound as claimed in claim 1 or claim 2,wherein R₄ is methyl.
 10. A compound as claimed in claim 1 or claim 2,wherein R₄ is hydrogen.
 11. A compound as claimed in claim 1 or claim 2,wherein R₅ represents hydrogen or C₁ -C₄ alkyl, or a group D-(C₁ -C₆alkyl) wherein D represents hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆ alkylthio,acylamino, optionally substituted phenyl, or a heterocyclic group.
 12. Acompound as claimed in claim 11, wherein R₅ is methyl.
 13. A compound asclaimed in claim 11 wherein R₅ is ethyl.
 14. A compound of the formula(I): ##STR17## or a pharmaceutically acceptable salt, solvate or hydratethereof, whereinR₂ is isobutyl, R₃ is cyclohexylmethyl or t-butyl, R₄ ishydrogen or methyl and R₅ is methyl or ethyl and wherein thestereochemistry of said compound is as follows:the carbon atom carryingthe hydroxy group and hydroxamic acid moiety --S, the carbon atomcarrying the R₂ group --R, the carbon atom carrying the R₃ group --S.15. N² - 3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹ methylamide, or a pharmaceutically acceptable salt, solvateor hydrate thereof.
 16. N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-tert-leucine-N.sup.1-methylamide, or a pharmaceutically acceptable salt, solvate or hydratethereof.
 17. A compound selected from the group consisting of;N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-oxymethylcarboxy)phenylalanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-phenylglycine-N.sup.1-methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-phenyl)phenylalanine-N¹ -methylamide; N³ -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!amino-1-azacyclotridecan-2-one;N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(1-pyrazolyl)alanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-4-(N-hydroxyamino)glutamicacid-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(2-thienyl)alanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹-(3-(2-pyrrolidone)propyl)amide,and pharmaceutically acceptable salts,solvates or hydrates thereof.
 18. A process for the preparation of acompound as claimed in claim 1, comprising:(a) coupling an acid ofgeneral formula (II): ##STR18## or an activated derivative thereof withhydroxylamine, O-protected hydroxylamine, or a salt thereof,wherein R₂represents a group R₆ --A-- wherein A represents a divalent straight orbranched, saturated or unsaturated hydrocarbon chain of up to 6 carbonatoms or said chain interrupted by an O or S atom, and R₆ representshydrogen or optionally substituted phenyl, C₃ -C₈ cycloalkyl or C₃ -C₈cycloalkenyl; R₃ represents a group R₇ --(B)_(n) -- wherein n is 0 or 1,B represents a divalent straight or branched, saturated or unsaturatedhydrocarbon chain of up to 6 carbon atoms or said chain interrupted byan O or S atom, and R₇ is --CONHOH, carboxyl, esterified or amidatedcarboxyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl, heterocyclyl, phenyl,napthyl, or substituted phenyl or napthyl in which the substituent(s)are selected from the group consisting of phenyl, hydroxy, C₁ -C₆alkoxy, benzyloxy, trifluoromethyl, halo and R₈ --(C═O)--(C₁ -C₆alkyl)--O-- wherein R₈ is hydroxy, amino, or an amino acid residuelinked via an amide bond; or (except when n=0) R₇ is hydrogen; R₄represents hydrogen or methyl; R₅ represents hydrogen; C₁ -C₆ alkyl; ora group D-(C₁ -C₆ alkyl) wherein D represents hydroxy, (C₁ -C₆) alkoxy,(C₁ -C₆) alkylthio, acylamino, optionally substituted phenyl, or aheterocyclic group, NH₂, or a mono- or di-(C₁ -C₆ alkyl) amino; or R₃and R₅ taken together represent a divalent, saturated or unsaturatedhydrocarbon chain of from 8-14 carbon atoms, or said chain interruptedby an O, S or N heteroatom; provided that R₃ is not the characteristicside chain of a natural alpha-amino acid, or the characteristic sidechain of a natural alpha-amino acid in which any functional substituentsare protected, any amino groups are acylated, and any carboxyl groupsare esterified, except that any substituent in R₂, R₃, R₄ and R₅, whichare potentially reactive with hydroxylamine, O-protected hydroxylamineor salts thereof may themselves be protected from such reaction, thenremoving any protective groups from the resultant hydroxamic acid moietyand from any protective substituents in R₂, R₃, R₄ and R₅ ; and (b)optionally converting a compound of formula (I) into another compound offormula (I).
 19. A process as claimed in claim 18 wherein an activatedderivative of a compound of formula (II) is used and said activatedderivative is a pentafluorophenyl, hydroxysuccinyl, orhydroxybenztriazyl ester.
 20. A process as claimed in claim 18 or claim19 wherein the compound of formula (II) is prepared by coupling an acidof formula (III) or an activated derivative thereof with an amine offormula (IV): ##STR19## wherein R₂ represents a group R₆ --A-- wherein Arepresents a divalent straight or branched, saturated or unsaturatedhydrocarbon chain of up to 6 carbon atoms or said chain interrupted byan O or S atom, and R₆ represents hydrogen or an optionally substitutedphenyl, C₃ -C₈ cycloalkyl or C₃ -C₈ cycloalkenyl group;R₃ represents agroup R₇ --(B)_(n) -- wherein n is 0 or 1, B represents a divalentstraight or branched, saturated or unsaturated hydrocarbon chain of upto 6 carbon atoms or said chain interrupted by an O or S atom, and R₇ is--CONHOH, carboxyl, esterified or amidated carboxyl, C₃ -C₈ cycloalkyl,C₃ -C₈ cycloalkenyl, heterocyclyl, phenyl, napthyl, or substitutedphenyl or napthyl in which the substituent(s) are selected from thegroup consisting of phenyl, hydroxy, C₁ -C₆ alkoxy, benzyloxy,trifluoromethyl, halo and R₈ --(C═O)--(C₁ -C6 alkyl)--O-- wherein R₈ ishydroxy, amino, or an amino acid residue linked via an amide bond; or(except when n=0) R₇ is hydrogen; R₄ represents hydrogen or methyl; R₅represents hydrogen; C₁ -C₆ alkyl; or a group D-(C₁ -C₆ alkyl) wherein Drepresents hydroxy, (C₁ -C₆) alkoxy, (C₁ -C₆) alkylthio, acylamino,optionally substituted phenyl, or a heterocyclic group, NH₂, or mono- ordi-(C₁ -C₆ alkyl) amino; or R₃ and R₅ taken together represent adivalent, saturated or unsaturated hydrocarbon chain of from 8-14 carbonatoms, or said chain interrupted by an O, S or N heteroatom; providedthat R₃ is not the characteristic side chain of a natural alpha-aminoacid, or the characteristic side chain of a natural alpha-amino acid inwhich any functional substituents are protected, any amino groups areacylated, and any carboxyl groups are esterified; and R₁₀ and R₁₁separately represent hydroxy protecting groups or taken togetherrepresent a divalent moiety which simultaneously protects both hydroxygroups, and subsequently removing the protecting groups or protectingmoiety.
 21. A process as claimed in claim 20 wherein an activatedderivative of a compound of formula (III) is used and said activatedderivative is a pentafluorophenyl ester, acid anhydride or acid halide.22. A process as claimed in claim 20 or claim 21 wherein compound (III)has the formula (V): ##STR20## wherein R₂ represents a group R₆ --A--wherein A represents a divalent straight or branched, saturated orunsaturated hydrocarbon chain of up to 6 carbon atoms or said chaininterrupted by an O or S atom, and R₆ represents hydrogen or anoptionally substituted phenyl, C₃ -C₈ cycloalkyl or C₃ -C₈ cycloalkenylgroup;R₃ represents a group R₇ --(B)_(n) -- wherein n is 0 or 1, Brepresents a divalent straight or branched, saturated or unsaturatedhydrocarbon chain of up to 6 carbon atoms or said chain interrupted byan O or S atom, and R, is --CONHOH, carboxyl, esterified or amidatedcarboxyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl, heterocyclyl, phenyl,napthyl, or substituted phenyl or napthyl in which the substituent(s)are selected from the group consisting of phenyl, hydroxy, C₁ -C₆alkoxy, benzyloxy, trifluoromethyl, halo and R₈ --(C═O)--(C₁ -C6alkyl)--O-- wherein R₈ is hydroxy, amino, or an amino acid residuelinked via an amide bond; or (except when n=0) R₇ is hydrogen; R₄represents hydrogen or methyl; R₅ represents hydrogen; C₁ -C₆ alkyl; ora group D-(C₁ -C₆ alkyl) wherein D represents hydroxy, (C₁ -C₆) alkoxy,(C₁ -C₆) alkylthio, acylamino, optionally substituted phenyl, or aheterocyclic group, NH₂, or mono- or di-(C₁ -C₆ alkyl) amino; or R₃ andR₅ taken together represent a divalent, saturated or unsaturatedhydrocarbon chain of from 8-14 carbon atoms, or said chain interruptedby an O, S or N heteroatom; provided that R₃ is not the characteristicside chain of a natural alpha-amino acid, or the characteristic sidechain of a natural alpha-amino acid in which any functional substituentsare protected, any amino groups are acylated, and any carboxyl groupsare esterified; and R₁₂ and R₁₃ are derived from a dioxalone formingreagent.
 23. A process as claimed in claim 22 wherein the groups R₁₂ andR₁₃ are hydrogen, alkyl, phenyl or substituted phenyl.
 24. Apharmaceutical composition useful for treating diseases or conditionsmediated by MMPs in human and animals and useful for inhibiting therelease of tumor necrosis factor from cells in humans and animalscomprising a therapeutically effective amount of a compound of theformula (I): ##STR21## or a pharmaceutically acceptable salt, solvate orhydrate thereof, whereinR₂ represents a group R₆ --A-- wherein Arepresents a divalent straight or branched, saturated or unsaturatedhydrocarbon chain of up to 6 carbon atoms or said chain interrupted byan O or S atom, and R₆ represents hydrogen or an optionally substitutedphenyl, C₃ -C₈ cycloalkyl or cycloalkenyl; R₃ represents a group R₇--(B)_(n) -- wherein n is 0 or 1, B represents a divalent straight orbranched, saturated or unsaturated hydrocarbon chain of up to 6 carbonatoms or said chain interrupted by an O or S atom, and R₇ is --CONHOH,carboxyl, esterified or amidated carboxyl, C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkenyl, heterocyclyl, phenyl, napthyl, or substituted phenyl ornapthyl in which the substituent(s) are selected from the groupconsisting of phenyl, hydroxy, C₁ -C₆ alkoxy, benzyloxy,trifluoromethyl, halo and R₈ --(C═O)--(C₁ -C6 alkyl)--O-- wherein R₈ ishydroxy, amino, or an amino acid residue linked via an amide bond; or(except when n=0) R₇ is hydrogen; R₄ represents hydrogen or methyl; R₅represents hydrogen; C₁ -C₆ alkyl; or a group D-(C₁ -C₆ alkyl) wherein Drepresents hydroxy, (C₁ -C₆) alkoxy, (C₁ -C₆) alkylthio, acylamino,optionally substituted phenyl, or a heterocyclic group, NH₂, or mono- ordi-(C₁ -C₆ alkyl) amino; or R₃ and R₅ taken together represent adivalent, saturated or unsaturated hydrocarbon chain of from 8-14 carbonatoms, or said chain interrupted by an O, S or N heteroatom; providedthat R₃ is not the characteristic side chain of a natural alpha-aminoacid, or the characteristic side chain of a natural alpha-amino acid inwhich any functional substituents are protected, any amino groups areacylated, and any carboxyl groups are esterified; in combination with apharmaceutically acceptable carrier.
 25. A pharmaceutical composition asclaimed in claim 24, wherein the stereochemistry of said compound is asfollows:the carbon atom carrying the hydroxy group and hydroxamic acidmoiety --S, the carbon atom carrying the R₂ group --R, the carbon atomcarrying the R₃ group --S.
 26. A pharmaceutical composition as claimedin claim 24 or claim 25 wherein R₂ represents C₃ -C₆ alkyl,cycloalkyl(C₃ -C₆ alkyl), phenyl(C₂ -C₆ alkyl), C₂ -C₄ alkoxy(C₁ -C₃alkyl), or C₂ -C₄ alkylsulphanyl(C₁ -C₃ alkyl).
 27. A pharmaceuticalcomposition as claimed in claim 26, wherein R₂ is isobutyl.
 28. Apharmaceutical composition as claimed in claim 24 or claim 25, whereinR₃ represents a phenyl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, phenyl(C₁ -C₆alkyl), substituted phenyl(C₁ -C₆ alkyl), C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkyl(C₁ -C₆ alkyl), thienyl, thienyl(C₁ -C₆ alkyl), pyridyl(C₁ -C₆alkyl), thiazolyl(C₁ -C₆ alkyl), thiofuranyl(C₁ -C₆ alkyl),benzothiofuranyl(C₁ -C₆ alkyl) or imidazolyl(C₁ -C₆ alkyl) group, or R₃and R₅ taken together may form a C₇ -C₁₂ alkylene chain, or saidalkylene chain interrupted by an O, S or N heteroatom.
 29. Apharmaceutical composition as claimed in claim 28, wherein R₃ representsphenyl, t-butyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl,optionally substituted phenylethyl, phenylpropyl, phenylbutyl orphenylpentyl in which the optional substituent(s) are in the phenyl ringand are selected from the group consisting of phenyl, hydroxy, C₁ -C₆alkoxy, benzyloxy, trifluoromethyl, halo and R₈ --(C═O)--(C₁ -C₆alkyl)--O-- wherein R₈ is hydroxy, amino, or an amino acid residuelinked via an amide bond.
 30. A pharmaceutical composition as claimed inclaim 28, wherein R₃ is t-butyl.
 31. A pharmaceutical composition asclaimed in claim 28, wherein R₃ is cyclohexylmethyl.
 32. Apharmaceutical composition as claimed in claim 24 or claim 25, whereinR₄ is methyl.
 33. A pharmaceutical composition as claimed in claim 24 orclaim 25, wherein R₄ is hydrogen.
 34. A pharmaceutical composition asclaimed in claim 31 or claim 32, wherein R₅ represents hydrogen or C₁-C₄ alkyl, or a group D-(C₁ -C₆ alkyl) wherein D represents hydroxy, (C₁-C₆)alkoxy, (C₁ -C₆)alkylthio, acylamino, optionally substituted phenyl,or a heterocyclic group.
 35. A pharmaceutical composition as claimed inclaim 34, wherein R₅ is methyl.
 36. A pharmaceutical composition asclaimed in claim 34, wherein R₅ is ethyl.
 37. A pharmaceuticalcomposition useful for treating diseases or conditions mediated by MMPsin human and animals and useful for inhibiting the release of tumornecrosis factor from cells in humans and animals comprising atherapeutically effective amount of a compound of the formula (I):##STR22## or a pharmaceutically acceptable salt, solvate or hydratethereof, whereinR₂ is isobutyl, R₃ is cyclohexylmethyl or t-butyl, R₄ ishydrogen or methyl, and R₅ is methyl or ethyl and wherein thestereochemistry of said compound is as follows:the carbon atom carryingthe hydroxy group and hydroxamic acid moiety --S, the carbon atomcarrying the R₂ group --R, the carbon atom carrying the R₃ group --S, incombination with a pharmaceutically acceptable carrier.
 38. Apharmaceutical composition useful for treating diseases or conditionsmediated by MMPs in humans and animals and useful for inhibiting therelease of tumor necrosis factor from cells in humans and animalscomprising a therapeutically effective amount of N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹ methylamide, or a pharmaceutically acceptable salt, solvateor hydrate thereof, in combination with a pharmaceutically acceptablecarrier.
 39. A pharmaceutical composition useful for treating diseasesor conditions mediated by MMPs in humans and animals and useful forinhibiting the release of tumor necrosis factor from cells in humans andanimals comprising a therapeutically effective amount of N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-tert-leucine-N.sup.1methylamide, or a pharmaceutically acceptable salt, solvate or hydratethereof, in combination with a pharmaceutically carrier.
 40. Apharmaceutical composition useful for treating diseases or conditionsmediated by MMPs in humans and animals and useful for inhibiting therelease of tumor necrosis factor from cells in humans and animalscomprising a therapeutically effective amount of a compound selectedfrom the group consisting of;N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-oxymethylcarboxy)phenylalanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-phenylglycine-N.sup.1-methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-phenyl)phenylalanine-N¹ -methylamide; N³ -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!amino-1-azacyclotridecan-2-one;N² - 3S -Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(1-pyrazolyl) alanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-4-(N-hydroxyamino)glutamicacid-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(2-thienyl)alanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹-(3-(2-pyrrolidone)propyl)amide,and pharmaceutically acceptable salts,solvates or hydrates thereof, in combination with a pharmaceuticallyacceptable carrier.
 41. A pharmaceutical composition as claimed in claim24 or claim 25 in oral administration form.
 42. A pharmaceuticalcomposition as claimed in claim 39 in oral administration form.
 43. Amethod of treating diseases or conditions mediated by MMPs in a human oranimal comprising administering to a human or animal in need thereof atherapeutically effective amount of a compound of the formula (I):##STR23## or a pharmaceutically acceptable salt, solvate or hydratethereof, whereinR₂ represents a group R₆ --A-- wherein A represents adivalent straight or branched, saturated or unsaturated hydrocarbonchain of up to 6 carbon atoms or said chain interrupted by an O or Satom, and R₆ represents hydrogen or an optionally substituted phenyl, C₃-C₈ cycloalkyl or cycloalkenyl; R₃ represents a group R₇ --(B)_(n) --wherein n is 0 or 1, B represents a divalent straight or branched,saturated or unsaturated hydrocarbon chain of up to 6 carbon atoms orsaid chain interrupted by an O or S atom, and R₇ is --CONHOH, carboxyl,esterified or amidated carboxyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl,heterocyclyl, phenyl, napthyl, or substituted phenyl or napthyl in whichthe substituent(s) are selected from the group consisting of phenyl,hydroxy, C₁ -C₆ alkoxy, benzyloxy, trifluoromethyl, halo and R₈--(C═O)--(C₁ -C6 alkyl)--O-- wherein R₈ is hydroxy, amino, or an aminoacid residue linked via an amide bond; or (except when n=0) R₇ ishydrogen; R₄ represents hydrogen or methyl; R₅ represents hydrogen; C₁-C₆ alkyl; or a group D-(C₁ -C₆ alkyl) wherein D represents hydroxy, (C₁-C₆) alkoxy, (C₁ -C₆) alkylthio, acylamino, optionally substitutedphenyl, or a heterocyclic group, NH₂, or mono- or di-(C₁ -C₆ alkyl)amino; or R₃ and R₅ taken together represent a divalent, saturated orunsaturated hydrocarbon chain of from 8-14 carbon atoms, or said chaininterrupted by an O, S or N heteroatom; provided that R₃ is not thecharacteristic side chain of a natural alpha-amino acid, or thecharacteristic side chain of a natural alpha-amino acid in which anyfunctional substituents are protected, any amino groups are acylated,and any carboxyl groups are esterified; in combination with apharmaceutically acceptable carrier.
 44. A method as claimed in claim43, wherein the stereochemistry of said compound is as follows:thecarbon atom carrying the hydroxy group and hydroxamic acid moiety --S,the carbon atom carrying the R₂ group --R, the carbon atom carrying theR₃ group --S.
 45. A method as claimed in claim 43 or claim 44, whereinR₂ represents C₃ -C₆ alkyl, C₃ -C₈ cycloalkyl(C₃ -C₆ alkyl), phenyl(C₂-C₆ alkyl), C₂ -C₄ alkoxy(C₁ -C₃ alkyl)_(m), or C₂ -C₄ alkylsulphanyl(C₁-C₃ alkyl).
 46. A method as claimed in claim 45, wherein R₂ is isobutyl.47. A method as claimed in claim 43 or claim 44, wherein R₃ represents aphenyl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, phenyl(C₁ -C₆ alkyl), substitutedphenyl(C₁ -C₆ alkyl), C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl(C₁ -C₆alkyl), thienyl, thienyl(C₁ -C₆ alkyl), pyridyl(C₁ -C₆ alkyl),thiazolyl(C₁ -C₆ alkyl), thiofuranyl(C₁ -C₆ alkyl), benzothiofuranyl(C₁-C₆ alkyl) or imidazolyl(C₁ -C₆ alkyl) group, or R₃ and R₅ takentogether may form a C₇ -C₁₂ alkylene chain, or said alkenyl interruptedby an O, S or N heteroatom.
 48. A method as claimed in claim 47, whereinR₃ represents phenyl, t-butyl, cyclohexylpropyl, cyclohexylbutylcyclohexylpentyl, optionally substituted phenylethyl, phenylpropyl,phenylbutyl or phenylpentyl in which the optional substituent(s) are inthe phenyl ring and are selected from the group consisting of phenyl,hydroxy, C₁ -C₆ alkoxy, benzyloxy, trifluoromethyl, halo and R₈--(C=O)--(C₁ -C₆ alkyl)--O-- wherein R₈ is hydroxy, amino, or an aminoacid residue linked via an amide bond.
 49. A method as claimed in claim47, wherein R₃ is t-butyl.
 50. A method as claimed in claim 47, whereinR₃ is cyclohexylmethyl.
 51. A method as claimed in claim 43 or claim 44,wherein R₄ is methyl.
 52. A method as claimed in claim 43 or claim 44,wherein R₄ is hydrogen.
 53. A method as claimed in claim 43 or claim 44,wherein R₅ represents hydrogen or C₁ -C₄ alkyl, or a group D-(C₁ -C₆alkyl) wherein D represents hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkylthio,acylamino, optionally substituted phenyl, or a heterocyclic group.
 54. Amethod as claimed in claim 53, wherein R₅ is methyl.
 55. A method asclaimed in claim 53, wherein R₅ is ethyl.
 56. A method of treatingdiseases or conditions mediated by MMPs in a human or animal comprisingadministering to a human or animal in need thereof a therapeuticallyeffective amount of a compound of the formula (I): ##STR24## or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinR₂is isobutyl, R₃ is cyclohexylmethyl or t-butyl, R₄ is hydrogen or methyland R₅ is methyl or ethyl and wherein the stereochemistry of saidcompound is as follows:the carbon atom carrying the hydroxy group andhydroxamic acid moiety --S, the carbon atom carrying the R₂ group --R,the carbon atom carrying the R₃ group --S, in combination with apharmaceutically acceptable carrier.
 57. A method of treating diseasesor conditions mediated by MMPs in a human or animal comprisingadministering to a human or animal in need thereof a therapeuticallyeffective amount of N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹ methylamide, or a pharmaceutically acceptable salt, solvateor hydrate thereof, in combination with a pharmaceutically acceptablecarrier.
 58. A method of treating diseases or conditions mediated byMMPs in a human or animal comprising administering to a human or animalin need thereof a therapeutically effective amount of N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-tert-leucine-N.sup.1-methylamide, or a pharmaceutically acceptable salt, solvate or hydratethereof, in combination with a pharmaceutically acceptable carrier. 59.A method of treating diseases or conditions mediated by MMPs in a humanor animal comprising administering to a human or animal in need thereofa therapeutically effective amount of a compound selected from the groupconsisting of;N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-oxymethylcarboxy)phenylalanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-phenylglycine-N.sup.1-methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-phenyl)phenylalanine-N¹ -methylamide; N³ -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!amino-1-azacyclotridecan-2-one;N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(1-pyrazolyl)-alanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-4-(N-hydroxyamino)glutamicacid-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(2-thienyl)alanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹-(3-(2-pyrrolidone)propyl)amide,and pharmaceutically acceptable salts,solvates or hydrates thereof, in combination with a pharmaceuticallyacceptable carrier.
 60. A method as claimed in claim 43 or claim 44,wherein the administration is oral.
 61. A method as claimed in claim 57,wherein the administration is oral.
 62. A method as claimed in claim 43,wherein said disease or condition is rheumatoid arthritis,osteoarthritis, periodontitis, gingivitis, corneal ulceration or tumormetastasis, invasion and growth.
 63. A method of inhibiting the releaseof TNF from cells in a human or animal comprising administering to ahuman or animal in need thereof a therapeutically effective amount of acompound of the formula (I): ##STR25## or a pharmaceutically acceptablesalt, solvate or hydrate thereof, whereinR₂ represents a group R₆ --A--wherein A represents a divalent straight or branched, saturated orunsaturated hydrocarbon chain of up to 6 carbon atoms or said chaininterrupted by an O or S atom, and R₆ represents hydrogen or anoptionally substituted phenyl, C₃ -C₈ cycloalkyl or cycloalkenyl; R₃represents a group R₇ --(B)_(n) -- wherein n is 0 or 1, B represents adivalent straight or branched, saturated or unsaturated hydrocarbonchain of up to 6 carbon atoms or said chain interrupted by an O or Satom, and R₇ is --CONHOH, carboxyl, esterified or amidated carboxyl, C₃-C₈ cycloalkyl, C₃ -C₈ cycloalkenyl, heterocyclyl, phenyl, napthyl, orsubstituted phenyl or napthyl in which the substituent(s) are selectedfrom the group consisting of phenyl, hydroxy, C₁ -C₆ alkoxy, benzyloxy,trifluoromethyl, halo and R₈ --(C═O)--(C₁ -C6 alkyl)--O-- wherein R₈ ishydroxy, amino, or an amino acid residue linked via an amide bond; or(except when n=0) R₇ is hydrogen; R₄ represents hydrogen or methyl; R₅represents hydrogen; C₁ -C₆ alkyl; or a group D-(C₁ -C₆ alkyl) wherein Drepresents hydroxy, (C₁ -C₆) alkoxy, (C₁ -C₆) alkylthio, acylamino,optionally substituted phenyl, or a heterocyclic group, NH₂, or mono- ordi-(C₁ -C₆ alkyl) amino; or R₃ and R₅ taken together represent adivalent, saturated or unsaturated hydrocarbon chain of from 8-14 carbonatoms, or said chain interrupted by an O, S or N heteroatom; providedthat R₃ is not the characteristic side chain of a natural alpha-aminoacid, or the characteristic side chain of a natural alpha-amino acid inwhich any functional substituents are protected, any amino groups areacylated, and any carboxyl groups are esterified; in combination with apharmaceutically acceptable carrier.
 64. A method as claimed in claim63, wherein the stereochemistry of said compound is as follows:thecarbon atom carrying the hydroxy group and hydroxamic acid moiety --S,the carbon atom carrying the R₂ group --R, the carbon atom carrying theR₃ group --S.
 65. A method as claimed in claim 63 or claim 64, whereinR₂ represents C₃ -C₆ alkyl, C₃ -C₈ cycloalkyl(C₃ -C₆ alkyl), phenyl(C₂-C₆ alkyl), C₂ -C₄ alkoxy(C₁ -C₃ alkyl)_(m), or C₂ -C₄ alkylsulphanyl(C₁-C₃ alkyl).
 66. A method as claimed in claim 65, wherein R₂ is isobutyl.67. A method as claimed in claim 63 or claim 64, wherein R₃ represents aphenyl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, phenyl(C₁ -C₆ alkyl), substitutedphenyl(C₁ -C₆ alkyl), C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl(C₁ -C₆alkyl), thienyl, thienyl(C₁ -C₆ alkyl), pyridyl(C₁ -C₆ alkyl),thiazolyl(C₁ -C₆ alkyl), thiofuranyl(C₁ -C₆ alkyl), benzothiofuranyl(C₁-C₆ alkyl) or imidazolyl(C₁ -C₆ alkyl) group, or R₃ and R₅ takentogether may form a C₇ -C₁₂ alkylene chain, or said alkylene interruptedby an O, S or N heteroatom.
 68. A method as claimed in claim 67, whereinR₃ represents phenyl, t-butyl, cyclohexylpropyl, cyclohexylbutyl,cyclohexylpentyl, optionally substituted phenylethyl, phenylpropyl,phenylbutyl or phenylpentyl in which the optional substituent(s) are inthe phenyl ring and are selected from the group consisting of phenyl,hydroxy, C₁ -C₆ alkoxy, benzyloxy, trifluoromethyl, halo and R₈--(C═O)--(C₁ -C₆ alkyl)--O-- wherein R₈ is hydroxy, amino, or an aminoacid residue linked via an amide bond.
 69. A method as claimed in claim67, wherein R₃ is t-butyl.
 70. A method as claimed in claim 67, whereinR₃ is cyclohexylmethyl.
 71. A method as claimed in claim 63 or claim 64,wherein R₄ is methyl.
 72. A method as claimed in claim 63 or claim 64,wherein R₄ is hydrogen.
 73. A method as claimed in claim 63 or claim 64,wherein R₅ represents hydrogen or C₁ -C₄ alkyl, or a group D-(C₁ -C₆alkyl) wherein D represents hydroxy, C₁ -C₆)alkoxy, (C₁ -C₆)alkylthio,acylamino, optionally substituted phenyl, or a heterocyclic group.
 74. Amethod as claimed in claim 73, wherein R₅ is methyl.
 75. A method asclaimed in claim 73, wherein R₅ is ethyl.
 76. A method of inhibiting therelease of TNF from cells in a human or animal comprising administeringto a human or animal in need thereof a therapeutically effective amountof a compound of the formula (I): ##STR26## or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, whereinR₂ is isobutyl, R₃is cyclohexylmethyl or t-butyl, R₄ is hydrogen or methyl and R₅ ismethyl or ethyl and wherein the stereochemistry of said compound is asfollows:the carbon atom carrying the hydroxy group and hydroxamic acidmoiety --S, the carbon atom carrying the R₂ group --R, the carbon atomcarrying the R₃ group --S,in combination with a pharmaceuticallyacceptable carrier.
 77. A method of inhibiting the release of TNF fromcells in a human or animal comprising administering to a human or animalin need thereof a therapeutically effective amount of N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹ methylamide, or a pharmaceutically acceptable salt, solvateor hydrate thereof, in combination with a pharmaceutically acceptablecarrier.
 78. A method of inhibiting the release of TNF from cells in ahuman or animal comprising administering to a human or animal in needthereof a therapeutically effective amount of N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-tert-leucine-N.sup.1-methylamide, or a pharmaceutically acceptable salt, solvate or hydratethereof, in combination with a pharmaceutically acceptable carrier. 79.A method of inhibiting the release of TNF from cells in a human oranimal comprising administering to a human or animal in need thereof atherapeutically effective amount of a compound selected from the groupconsisting of;N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-oxymethylcarboxy)phenylalanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-phenylglycine-N.sup.1-methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-(4-phenyl)phenylalanine-N¹ -methylamide; N³ -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!amino-1-azacyclotridecan-2-one;N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(1-pyrazolyl)alanine-N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-4-(N-hydroxyamino)glutamicacid-N¹ methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-3-(2-thienyl)alanine- N¹ -methylamide; N² -3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl!-L-cyclohexylalanine-N¹-(3-(2-pyrrolidone)propyl)amide,and pharmaceutically acceptable salts,solvates or hydrates thereof, in combination with a pharmaceuticallyacceptable carrier.
 80. A method as claimed in claim 63 or claim 64,wherein the administration is oral.
 81. A method as claimed in claim 77,wherein the administration is oral.
 82. A method as claimed in claim 63,which comprises treating inflammation, fever, congestive heart failure,hemorrhage, blood, coagulation, acute phase response, or cachexia.